Ongoing-Studies

We have several ongoing studies including:

1). In Vivo metabolism of amyloid-beta (Aβ) in Alzheimer’s disease (AD)
We have pioneered a novel stable isotope labeling kinetics (SILK) technique that measures Aβ metabolism in humans. To measure the production and clearance of Aβ in AD, we developed a method to measure human CNS Aβ production and clearance, and compared Aβ42 and Aβ40 production and clearance rates in individuals with symptomatic AD and cognitively normal persons to determine if either or both is altered in AD. This initial study demonstrates the average clearance rate of Aβ42 was slower for AD individuals compared with cognitively normal controls (5.3%/hr vs. 7.6%/hr, p=0.03), as was the average clearance rate of Aβ40 (5.2%/hr for AD individuals vs. 7.0%/hr for controls; p=0.01). (Figure 1 from Mawuenyega et al., 2011 Science; below).

Aβ kinetics in the CNS of twelve AD participants (red triangles) and twelve controls (blue circles). The amount of labeled Aβ42 and Aβ40 was measured and compared between groups to measure production and clearance rates of both Aβ species. (A) The average normalized labeled Aβ42 time course. (B) Aβ42 clearance rate during the clearance phase (hours 24–36). (C) Normalized labeled Aβ40 time course. (D) Aβ40 clearance in AD compared to controls. (E) The average fractional synthesis rates of Aβ42 and Aβ40 in AD participants and cognitively normal controls. (F) The average fractional clearance rates of Aβ42 and Aβ40.

In follow up studies using the SILK method, we demonstrate a highly significant correlation between increasing age and slowed Aβ turnover rates (2.5-fold longer half-life over five decades of age). In addition, we found independent effects on Aβ42 kinetics specifically in participants with amyloid deposition. Amyloidosis was associated with a higher (>50%) irreversible loss of soluble Aβ42 and a 10-fold higher Aβ42 reversible exchange rate. (Figure 1 from Patterson et al., 2015, Annals of Neurology; below).

2.) Longitudinal changes that occur in Autosomal Dominant Alzheimer Disease (ADAD):Increased in vivo amyloid-β42 production, exchange, and loss in presenilin mutation carriers. We are investigating the changes that occur in ADAD including structural changes by MRI, pathological changes by PET-PIB, functional changes by Clinical Dementia Rating and neuropsychometric testing, and pathophysiological changes in CSF biomarkers and CNS protein production and clearance rates. We found that CNS Aβ42 to Aβ40 production rates were 24% higher in mutation carriers compared to noncarriers, and this was independent of fibrillar amyloid deposits quantified by PET PIB imaging. Furthermore, the fractional turnover rate of soluble Aβ42 relative to Aβ40 was 65% faster in mutation carriers and correlated with amyloid deposition, consistent with increased deposition of Aβ42 into plaques, leading to reduced recovery of Aβ42 in cerebrospinal fluid (CSF). These findings support the hypothesis that Aβ42 is overproduced in the CNS of humans with PSEN mutations that cause AD, and demonstrate that soluble Aβ42 turnover and exchange processes are altered in the presence of amyloid plaques, causing a reduction in Aβ42 concentrations in the CSF. (Figure 1 from Potter et al., 2013, Science and Translational Medicine; below).

3.) In vivo strategies to assess disease-modifying therapies for Alzheimer disease
Pharmacodynamic response of proposed disease-modifying therapies for Alzheimer disease are tested by directly measuring the production, clearance and steady-state levels of the targeted proteins, including amyloid-beta. These studies quantitate targeted activity of therapeutics and provide evidence that these compounds may be effective in humans. (Figure 4 from Dobrowolska et al. 2014, Journal of Neuroscience; below)

4.) CNS derived proteomics and measurements
We are currently investigating multiple other CNS derived proteins and are developing methods to measure hundreds of protein metabolism profiles in humans using highly sensitive nano-flow mass spectrometry and in vivo labeling techniques. Advanced bio-informatics, cutting edge mass spectrometry, and in vivo and in vitro labeling experiments are used for highly quantitative analysis of proteins.